The Muenke syndrome mutation (FgfR3P244R) causes cranial base shortening associated with growth plate dysfunction and premature perichondrial ossification in murine basicranial synchondroses.

Abstract

Muenke syndrome caused by the FGFR3(P250R) mutation is an autosomal dominant disorder mostly identified with coronal suture synostosis, but it also presents with other craniofacial phenotypes that include mild to moderate midface hypoplasia. The Muenke syndrome mutation is thought to dysregulate intramembranous ossification at the cranial suture without disturbing endochondral bone formation in the skull. We show in this study that knock-in mice harboring the mutation responsible for the Muenke syndrome (FgfR3(P244R)) display postnatal shortening of the cranial base along with synchondrosis growth plate dysfunction characterized by loss of resting, proliferating and hypertrophic chondrocyte zones and decreased Ihh expression. Furthermore, premature conversion of resting chondrocytes along the perichondrium into prehypertrophic chondrocytes leads to perichondrial bony bridge formation, effectively terminating the postnatal growth of the cranial base. Thus, we conclude that the Muenke syndrome mutation disturbs endochondral and perichondrial ossification in the cranial base, explaining the midface hypoplasia in patients.

• Authors: Jason Laurita, Eiki Koyama, Bianca Chin, Jesse A Taylor, Gregory E Lakin, Kurt D Hankenson, Scott P Bartlett, Hyun-Duck Nah
• Journal: Developmental dynamics : an official publication of the American Association of Anatomists (Dev Dyn) Vol. 240 Issue 11 Pg. 2584-96 (Nov 2011) ISSN: 1097-0177 [Electronic] United States
• PMID: 22016144 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Wiley Periodicals, Inc.

Chemical References

• Arginine
• Proline
• Fgfr3 protein, mouse
• Receptor, Fibroblast Growth Factor, Type 3

Topics

• Amino Acid Substitution (physiology)
• Animals
• Arginine (genetics)
• Cranial Sutures (abnormalities, diagnostic imaging, metabolism, pathology)
• Craniosynostoses (genetics)
• Growth Plate (diagnostic imaging, metabolism)
• Mice
• Mice, Transgenic
• Models, Biological
• Mutation, Missense (physiology)
• Ossification, Heterotopic (genetics)
• Osteogenesis (genetics)
• Phenotype
• Proline (genetics)
• Receptor, Fibroblast Growth Factor, Type 3 (genetics, physiology)
• Skull Base (abnormalities, diagnostic imaging, metabolism)
• X-Ray Microtomography